CCN
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Crit Care Nurse 2004 Dec; 24(6): 40-45
This Article
Right arrow Full Text (PDF)
Right arrow Respond to This Article
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tazbir, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tazbir, J.

Clinical Article

Sepsis and the Role of Activated Protein C

Janice Tazbir, RN, MS, CCRN

Janice Tazbir has been a critical care nurse for 19 years, mostly at the University of Chicago Hospitals, Chicago, Ill. She has been a professor at Purdue University Calumet, Hammond, Ind, for 6 years. Her areas of teaching include advanced medical/surgical and critical care nursing.

To purchase reprints, contact The InnoVision Group, 101 Columbia, Aliso Viejo, CA 92656. Phone, (800) 809-2273 or (949) 362-2050 (ext 532); fax, (949) 362-2049; e-mail, reprints{at}aacn.org.

The term sepsis is derived from the Greek word sepien meaning "to make rotten."1 In 2001, 1.3% of all deaths in the United States were attributed to sepsis, and sepsis was the 10th leading cause of death.2 According to preliminary data for 2003, septicemia remains the 10th leading cause of death.3 The estimated annual costs of treating sepsis are approximately $17 billion, and sepsis affects more than 700000 patients in the United States each year.4

The most common sources of infection leading to sepsis include pulmonary and urinary sites, wounds, and invasive catheters.5 In a recent study6 of the epidemiology of sepsis in medical centers, of all patients diagnosed with sepsis, 55% were in intensive care units at the time of the onset of sepsis. Overall hospital mortality was 45%, which is similar to mortality data from sepsis historically.6 Sepsis and its sequelae are the leading causes of death in noncardiac intensive care units.7 Sepsis will continue as a major concern as the number of elderly persons increases with the graying of baby boomers, increasing numbers of sophisticated invasive procedures, and the emergence of drug-resistant strains of bacteria.5

Current attempts to treat sepsis have not resulted in acceptable mortality rates. Current standard treatment involves administration of antimicrobial agents and supportive care, including volume resuscitation and vasopressor therapy to maintain adequate blood pressure, blood components to treat coagulopathies, inotropic therapy to maintain cardiac contractility, and oxygen delivery to help prevent tissue hypoperfusion.8 If specific organ failure occurs, such as acute tubular necrosis or acute respiratory distress syndrome, it is treated with supportive care as required.

Of note, sepsis differs greatly from infection. Sepsis is defined as systemic inflammatory response syndrome with presumed or confirmed infection, and the term covers a clinical syndrome that occurs in response to an infection.9 Until recently, much controversy existed over terminology related to sepsis. In 1991, The American College of Chest Physicians/ Society of Critical Care Medicine consensus conference created and clearly agreed on definitions of sepsis9 (Table 1Go). The dynamic nature of sepsis is not fully understood, and much research is being done to better understand the pathogenesis of this syndrome.10–12


View this table:
[in this window]
[in a new window]
  		Table 1 Definitions from the 1991 American College of Chest Physicians/Society of Critical Care Medicine consensus conference9

 
Sepsis is a complex response involving many chemical and biological factors, and the responses are greatly individualized. For example, 2 persons may become infected with the same organism in the same location, such as bacterial infection of the urinary tract by Escherichia coli. Signs and symptoms may develop in both persons, and both may be treated with the same antimicrobial agent. One person may fully recover in days; in the other, sepsis may develop and the person may die of the syndrome. What happens in sepsis? Why is it so deadly?

The purpose of this article is to provide a clearer understanding of the pathogenesis of sepsis, explain the role of activated protein C (APC) in sepsis, and describe a new treatment option. The following is not a complete explanation of sepsis, but a "nuts and bolts" approach to describing the major processes. Information on the role of APC, a natural component of the anticoagulant system, is included because of an increased understanding of the role of APC in sepsis and the development of new treatments that involve the protein.


   Pathophysiology of Sepsis
Top
 Pathophysiology of Sepsis
Actions of APC
 Clinical Implications and...
 References
 Bibliography
 
In the current scientific model, sepsis is considered a 3-pronged cascade that occurs in response to infection. The 3 principal actions are inflammation, coagulation, and fibrinolysis.

When an infection occurs, the infectious agent produces endotoxins and exotoxins that induce cellular responses. These responses initiate a cascade of events that cause inflammation and cellular injury. Mast cells are activated and release cellular components, such as histamine. Histamine release causes vascular effects that produce constriction of arterioles and then vasodilatation near the injured area. These actions increase vascular permeability, allowing an exudate to form. Neutrophils and eosinophils release chemotactic factors and promote phagocytosis. Inflammation is further enhanced by the complement system, which is activated by antigen-antibody complexes (classic pathway) or by gram-negative bacteria and fungal wall polysaccharides (alternative pathway).13 Cytokines, including tumor necrosis factor and interleukins 1, 6, and 8, are released and lead to massive inflammation and endothelial dysfunction.11 Inflammation is normally useful in infection because it helps localize the effect of the toxin and induce a response to kill the invading organism. When inflammation is extreme, it leads to vascular congestion, endothelial injury, and overstimulation of the coagulation system.

Coagulation is closely associated with inflammation in sepsis. Many of the previously mentioned inflammatory mediators promote endothelial injury that promote coagulation indirectly or directly. Cytokines activate tissue factor, which is the principal activator of coagulation.14 The endothelial injury caused by the inflammation activates coagulation factor XII when blood comes into contact with vascular surfaces.13 Tissue factor and factor XII cause a domino effect of activating factors and result in thrombin generation. Thrombin converts soluble fibrinogen to fibrin. Fibrin clumps with platelets and forms clots. Coagulation is normally helpful in infection because it attempts to repair damaged vessels and prevent microvascular damage. In sepsis, coagulation produces thrombi that may act as emboli that block the microvasculature throughout the body, causing cellular death and ultimately inducing organ dysfunction.

Endothelial injury and inflammation inhibit fibrinolysis. Specifically, cytokines stimulate the release of plasminogen activator inhibitor-1 from platelets and endothelial surfaces. Plasminogen activator inhibitor-1 inhibits the release of tissue plasminogen activator, which normally activates plasmin, which is primarily responsible for fibrinolysis or breaking down of clots.15 Thrombin increases inflammation and inhibits fibrinolysis by activating thrombin-activatable fibrinolysis inhibitor.15 These actions prevent fibrinolysis, which normally occurs to create equilibrium between clot formation and breakdown. The balance of coagulation and fibrinolysis normally allows the body to exist in a steady-state in which thrombi are formed and broken down.16 This balance allows normal clotting free from bleeding disorders and excessive formation of thrombi (Figure 1Go).



View larger version (26K):
[in this window]
[in a new window]
  		Figure 1 Infection without sepsis.

 
Another reason for the increased formation of thrombi in sepsis is the decrease in the circulating level of APC17 (Figure 2Go). In sepsis, thrombin does not bind to thrombomodulin as readily, and therefore protein C does not become activated, so the circulating level of APC is decreased. Low serum levels of APC are associated clinically with sepsis, disseminated intravascular coagulopathy, multiorgan dysfunction, and increased mortality.



View larger version (27K):
[in this window]
[in a new window]
  		Figure 2 Infection with sepsis.

 
Currently, investigators are attempting to discover ways to decrease mortality associated with sepsis. The goal is a treatment that will decrease the inflammation and maintain balance between coagulation and fibrinolysis.


   Actions of APC
Top
 Pathophysiology of Sepsis
 Actions of APC
Clinical Implications and...
 References
 Bibliography
 
Protein C is a natural component of the anticoagulant system. Because of its antithrombotic properties, APC has been used to treat congenital protein C deficiency with neonatal thrombosis and purpura fulminans, warfarin-induced skin necrosis, and disseminated intravascular coagulation.18 Its use in reperfusing coronary vessels is being investigated.18–20 Figure 3Go summarizes the role of APC in sepsis.



View larger version (53K):
[in this window]
[in a new window]
  		Figure 3 A network of cascading events.

 
In sepsis, APC attempts to achieve homeostasis by decreasing inflammation, decreasing coagulation, and increasing fibrinolysis.14 Protein C circulates in the body in an inactive form. Protein C is altered from its inactive form to the activated form when thrombin binds with thrombomodulin.15 Thrombomodulin is a membrane glycoprotein that is expressed on epithelial cells. When it binds with thrombin, thrombomodulin is a cofactor for protein C activation. When bound to thrombomodulin, thrombin no longer converts fibrinogen to fibrin. As a result, coagulant activity is decreased, the ability of thrombin to activate platelets is blocked, and thrombolysis is prevented. Decreased inflammation is achieved by inhibiting cytokine production and release and by inhibiting neutrophil activation and endothelial damage. In addition, when protein C becomes APC, thrombin is inhibited and thrombin-mediated inflammatory effects are prevented. APC inhibits tissue factor, decreasing thrombin production and inactivating factors Va and VIII, changes that decrease coagulation. APC promotes fibrinolysis by inactivating plasminogen activator inhibitor-1 and inhibiting activation of thrombin-activatable fibrinolysis inhibitor.

In 2001, the results of the phase 3 worldwide evaluation of treatment with recombinant human APC in severe sepsis (the PROWESS study) were published.16 The purpose of the study was to determine if treatment with recombinant human APC reduced the rate of death from any cause among adult patients with severe sepsis. The study was a double-blind, placebo-controlled, multicenter trial with 1690 patients in 164 centers in 11 countries, and groups were stratified and randomized. Primary statistical analysis was based on a Cochran-Mantel-Haenzel test in which the groups were stratified by using the baseline covariates of severity of disease (based on Acute Physiology and Chronic Health Evaluation II scores), age, and plasma levels of protein C activity. Approximately 80% of the patients in the study were deficient in protein C. Patients with severe sepsis as defined by the 1991 American College of Chest Physicians/Society of Critical Care Medicine consensus conference (Table 1Go) were randomized. The control group received aggressive care and a placebo, and the treatment group received aggressive care and recombinant human APC intravenously at 24 µg/kg per hour for 96 hours. The study protocol did not have a standardized approach or definition of aggressive care or critical care support.

Enrollment in the study was suspended at the second interim analysis of data because the difference in mortality rates between the 2 groups exceeded the a priori guideline for stopping the trial. The mortality rate was 30.8% in the placebo group and 24.7% in the group given recombinant human APC. This difference indicates an absolute reduction in the risk of death of 6.1% (P=.005). The only serious potential side effect in the treatment group was a higher rate of serious bleeding (3.5% of patients vs 2.0% of patients in the control group, P=.06).

The results from this single study suggest a new treatment option for sepsis. Recombinant human APC therapy may be useful in decreasing mortality from sepsis. Currently, many centers are using recombinant human APC, drotrecogin alfa (activated), to treat sepsis (see Case Study).


   Clinical Implications and Administration of Drotrecogin Alfa (Activated)
Top
 Pathophysiology of Sepsis
 Actions of APC
 Clinical Implications and...
References
 Bibliography
 
Treatment with drotrecogin alfa (activated), a recombinant form of human APC, is used to reduce mortality in adult patients with severe sepsis who have a high risk of death as indicated by scores on the Acute Physiology and Chronic Health Evaluation II. Its efficacy has not been established in adults with severe sepsis and a lower risk of death or in children. Contraindications for treatment with drotrecogin alfa (activated) include active internal bleeding, recent brain or spinal surgery, head trauma or hemorrhagic stroke, trauma, intracranial neoplasm, evidence of cerebral herniation, known hypersensitivity to drotrecogin alfa (activated), and the presence of an epidural catheter.20 Bleeding is the most common adverse reaction to drotrecogin alfa (activated). Table 2Go lists conditions that warrant careful clinical consideration in evaluating the risks and benefits of treatment with drotrecogin alfa (activated) for individual patients.20


View this table:
[in this window]
[in a new window]
  		Table 2 Conditions that warrant consideration with drotrecogin alfa (activated) therapy20

 
The drug is administered intravenously at a rate of 24 µg/kg per hour for 96 hours. Drotrecogin alfa (activated) is supplied in 5- and 20-mg vials. The vials must be reconstituted with sterile water. Once the drug is reconstituted, the vial must be used within 3 hours. Drotrecogin alfa (activated) is further diluted with isotonic sodium chloride solution to a final concentration of 100 to 1000 µg/mL, and administration must be completed within 12 hours after preparation. The solution should be administered centrally by using an intravenous infusion pump. The infusion should be visually inspected for discoloration or particles before administration. Drotrecogin alfa (activated) should be administered via a dedicated catheter or through the same catheter as plain isotonic sodium chloride solution, lactated Ringer solution, or dextrose solution. Drotrecogin alfa (activated) infusions should be protected from direct sunlight and heat in excess of 30°C. Any questions about compatibility with other medications or administration should be directed to a pharmacist.

Coagulation status should be monitored during therapy. Most patients with severe sepsis have a degree of coagulopathy associated with a prolonged activated partial thromboplastin time; therefore activated partial thromboplastin time should not be used to assess coagulation status during drotrecogin alfa (activated) therapy.20 Drotrecogin alfa (activated) has a minimal effect on the prothombin time.20 Therefore, routine laboratory monitoring of the coagulation status of patients receiving the drug should include prothrombin time and a complete blood cell count approximately every 6 hours during therapy or as requested by a physician. Healthcare providers may request additional laboratory tests to monitor coagulation status, such as platelet counts, assays of the level of D-dimers, determination of the international normalized ratio, assays of specific coagulation factors, and disseminated intravascular coagulopathy profile. Any changes from baseline values should reported to the healthcare provider.

Go



View larger version (97K):
[in this window]
[in a new window]
 
 
If bleeding is suspected because a patient’s hemodynamic status is unstable or overt signs of bleeding are present, coagulation laboratory tests should be performed as needed. Nurses should verify that patients have a type and screen before receiving drotrecogin alfa (activated). Frequent neurological assessments are required because a decrease in level of consciousness or a change in neurological status may indicate intracerebral hemorrhage. Any change in neurological status should be reported immediately to the healthcare provider. If active bleeding develops, the infusion should be discontinued immediately and the healthcare provider should be notified.20 If an infusion is accidentally discontinued, it should be restarted at a rate of 24 µg/kg per hour; no bolus dose should be given. If a patient receiving drotrecogin alfa (activated) requires surgery, the infusion should be discontinued at least 2 hours before the surgery.

Limitations to the use of recombinant human APC include cost (approximately $6800 for the 96 hours of recommended therapy).21 In addition, it is approved only for treatment of adults with severe sepsis and a high risk of death, and the results are based on a single study without reproduced results.20

Critical care nurses must keep abreast of the information on sepsis to better care for patients who have this syndrome. It is through an improved awareness of sepsis that new treatments and their effects are appreciated. Informed nurses aid in the early recognition and treatment of sepsis and may facilitate decreasing the number of patients in the intensive care unit who die of sepsis each year.


   Acknowledgments
 
I thank my family, the Tazbir team, for their continued support and Tracy Blair for her thoughtful review of the manuscript.


   References
Top
 Pathophysiology of Sepsis
 Actions of APC
 Clinical Implications and...
 References
Bibliography
 

  1. The American Heritage Dictionary of the English Language. 4th ed. Boston, Mass; Houghton Mifflin Co; 2000.
  2. Centers for Disease Control and Prevention. Deaths: final data for 2001. National Vital Statistics Report. 2003;52:1–6. Available at: http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_03.pdf. Accessed October 4, 2004.
  3. Centers for Disease Control and Prevention. Deaths: preliminary data for 2002. National Vital Statistics Report. 2004:52:1–5. Available at: http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_13.pdf. Accessed October 4, 2004.
  4. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–1310.[Medline]
  5. Balk RA, Ely EW, Goyette RE. Sepsis Handbook. Nashville, Tenn: National Initiative in Sepsis Education, Vanderbilt University Medical Center; 2001:2–13.
  6. Sands KE, Bates DW, Lanken PN, et al. Epidemiology of sepsis syndrome in 8 academic medical centers. Academic Medical Center Consortium Sepsis Project Working Group. JAMA. 1997;278:234–240.[Abstract]
  7. Marshall JC, Cook DJ, Christou NC, Bernard GR, Sprung CL, Sibbald WJ. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med. 1995;23:1638–1652.[Medline]
  8. Jindal N, Hollenberg SM, Dellinger RP. Pharmacologic issues in the management of septic shock. Crit Care Clin. 2000;16:233–249.[Medline]
  9. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101:1644–1655.[Abstract/Free Full Text]
  10. Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest. 1997;112:235–243.[Free Full Text]
  11. Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med. 1999; 340:207–213.[Free Full Text]
  12. Rote NS. Inflammation. In: McCance KL, Huether SE, eds. Pathophysiology: the Biological Basis for Disease in Adults and Children. 4th ed. St Louis, Mo: Mosby; 2001:197–222.
  13. Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999; 341:586–592.[Free Full Text]
  14. Esmon CT. Molecular events that control the protein C anticoagulant pathway. Thromb Haemost. 1993;70:29–35.[Medline]
  15. Matthay MA. Severe sepsis: a new treatment with both anticoagulant and anti-inflammatory properties. N Engl J Med. 2001;344:759–762.[Free Full Text]
  16. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699–709.[Abstract/Free Full Text]
  17. Dreyfus M, Masterson M, David M, et al. Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency. Semin Thromb Hemost. 1995; 21:371–381.[Medline]
  18. Muller FM, Ehrenthal W, Hafner G, Schranz D. Purpura fulminans in severe congenital protein C deficiency: monitoring of treatment with protein C concentrate. Eur J Pediatr. 1996;155:20–25.[Medline]
  19. Jackson CV, Bailey BD, Shetler TJ. Pharmacological profile of recombinant, human activated protein C (LY203638) in a canine model of coronary artery thrombosis. J Pharmacol Exp Ther. 2000;29:967–971.
  20. Eli Lilly & Co. Information on drotrecogin alfa (activated). Available at: www.xigris.com. Accessed September 24, 2004.
  21. Shook D. A shock to Lilly’s system? Business Week Online. March 7, 2002. Available at: http://www.businessweek.com/bwdaily/dnflash/mar2002/nf2002037_2428.htm. Accessed September 24, 2004.

   Bibliography
Top
 Pathophysiology of Sepsis
 Actions of APC
 Clinical Implications and...
 References
 Bibliography
 
Astiz ME, Racknow EC. Septic shock. Lancet. 1998;351:1501–1505.[Medline]

Bone R. Sepsis, sepsis syndrome, and the systemic inflammatory response syndrome (SIRS). JAMA. 1995;273:155–156.[Medline]

Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM consensus on sepsis and organ failure. Chest. 1992;101:1481–1483.[Free Full Text]

Cohen J, Guyatt G, Bernard GR, et al. New strategies for clinical trials in patients with sepsis and septic shock. Crit Care Med. 2001;29:880–886.[Medline]

Eli Lilly & Co. Sepsis.com. Available at www.sepsis.com. Accessed September 24, 2004.

Grinnell BW, Joyce D. Recombinant human activated protein C: a system modulator of vascular function for treatment of severe sepsis. Crit Care Med. 2001;29(7 suppl):S53–S60.[Medline]

Gross PL, Aird WC. The endothelium and thrombosis. Semin Thromb Hemost. 2000;26:463–478.[Medline]

Increase in National Hospital Discharge Survey Rates for Septicemia—United States, 1979–1987. MMWR Morb Mortal Wkly Rep. 1990;39:31–34.[Medline]

Mesters MD, Helterbrand J, Utterback BG, et al. Prognostic value of protein C concentrations in neutropenic patients at high risk of severe septic complications. Crit Care Med. 2000;28:2209–2216.[Medline]

Padkin A, Rowan K, Black N. Using high quality clinical databases to complement the results of randomized controlled trials: the case of recombinant human activated protein C. BMJ. 2001;323:923–926.[Free Full Text]

Rangel-Frausto SM, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS): a prospective study. JAMA. 1995;273:117–123.[Abstract]

Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med. 1999;340:207–213.





This Article
Right arrow Full Text (PDF)
Right arrow Respond to This Article
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tazbir, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tazbir, J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS